Towards a New 3Rs Era in the construction of 3D cell culture models simulating tumor microenvironment

The tumor microenvironment significantly influences therapeutic response and clinical outcome. Microenvironment-mediated drug resistance can be induced by soluble factors secreted by tumor or stromal cells. The adhesion of tumor cells to stromal fibroblasts or to components of the extracellular matrix can also blunt therapeutic response. Microenvironment-targeted therapy strategies include inhibition of the extracellular ligand-receptor interactions and downstream pathways. Immune cells can both improve and obstruct therapeutic efficacy and may vary in their activation status within the tumor microenvironment; thus, re-programme of the immune response would be substantially more beneficial. The development of rational drug combinations that can simultaneously target tumor cells and the microenvironment may represent a solution to overcome therapeutic resistance.

Tumor-associated macrophages (TAMs) represent one of the main tumor-infiltrating immune cell types and are generally categorized into either of two functionally contrasting subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. The former typically exerts anti-tumor functions, including directly mediate cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) to kill tumor cells; the latter can promote the occurrence and metastasis of tumor cells, inhibit T cell-mediated anti-tumor immune response, promote tumor angiogenesis, and lead to tumor progression. Both M1 and M2 macrophages have high degree of plasticity and thus can be converted into each other upon tumor microenvironment changes or therapeutic interventions. As the relationship between TAMs and malignant tumors becoming clearer, TAMs have become a promising target for developing new cancer treatment. In this review, we summarize the origin and types of TAMs, TAMs interaction with tumors and tumor microenvironment, and up-to-date treatment strategies targeting TAMs.

Bioprinting is a 3D fabrication technology used to precisely dispense cell-laden biomaterials for the construction of complex 3D functional living tissues or artificial organs. While still in its early stages, bioprinting strategies have demonstrated their potential use in regenerative medicine to generate a variety of transplantable tissues, including skin, cartilage, and bone. However, current bioprinting approaches still have technical challenges in terms of high-resolution cell deposition, controlled cell distributions, vascularization, and innervation within complex 3D tissues. While no one-size-fits-all approach to bioprinting has emerged, it remains an on-demand, versatile fabrication technique that may address the growing organ shortage as well as provide a high-throughput method for cell patterning at the micrometer scale for broad biomedical engineering applications. In this review, we introduce the basic principles, materials, integration strategies and applications of bioprinting. We also discuss the recent developments, current challenges and future prospects of 3D bioprinting for engineering complex tissues. Combined with recent advances in human pluripotent stem cell technologies, 3D-bioprinted tissue models could serve as an enabling platform for high-throughput predictive drug screening and more effective regenerative therapies.